title: Modulation of macrophage phenotype by cell shape.
abstract: Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Although much is known about how soluble factors influence macrophage polarization, relatively little is known about how physical cues present in the extracellular environment might modulate proinflammatory (M1) vs. prohealing (M2) activation. Specifically, the role of cell shape has not been explored, even though it has been observed that macrophages adopt different geometries in vivo. We and others observed that macrophages polarized toward different phenotypes in vitro exhibit dramatic changes in cell shape: M2 cells exhibit an elongated shape compared with M1 cells. Using a micropatterning approach to control macrophage cell shape directly, we demonstrate here that elongation itself, without exogenous cytokines, leads to the expression of M2 phenotype markers and reduces the secretion of inflammatory cytokines. Moreover, elongation enhances the effects of M2-inducing cytokines IL-4 and IL-13 and protects cells from M1-inducing stimuli LPS and IFN-γ. In addition shape- but not cytokine-induced polarization is abrogated when actin and actin/myosin contractility are inhibited by pharmacological agents, suggesting a role for the cytoskeleton in the control of macrophage polarization by cell geometry. Our studies demonstrate that alterations in cell shape associated with changes in ECM architecture may provide integral cues to modulate macrophage phenotype polarization.
authors.affiliation: Departments of Biomedical Engineering and Chemical Engineering and Materials Science, and The Edwards Lifesciences Center for Advanced Cardiovascular Technology, University of California, Irvine, CA 92697.
authors.forename: Frances Y
authors.initials: FY
authors.lastname: McWhorter
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.forename: Phoebe
authors.initials: P
authors.lastname: Nguyen
authors.forename: Thanh
authors.initials: T
authors.lastname: Chung
authors.forename: Wendy F
authors.initials: WF
authors.lastname: Liu
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000276:immunology / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology; D015415:Biomarkers / Q000032:analysis* / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology; D048430:Cell Shape / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D016130:Immunophenotyping / Q000379:methods; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism
chemical_list: D000577:Amides; D001381:Azepines; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D018793:Interleukin-13; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011725:Pyridines; D011956:Receptors, Cell Surface; C056218:ML 9; C108830:Y 27632; C079109:N-(3-pyridylmethyl)adriamycin; D015847:Interleukin-4; D015638:Cytochalasin D; D004317:Doxorubicin; D007371:Interferon-gamma; D009219:Myosin-Light-Chain Kinase; C574619:ARG1 protein, human; D001119:Arginase